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Intrapulmonary IFN-ß Gene Therapy Using an Adenoviral Vector Is Highly Effective in a Murine Orthotopic Model of Bronchogenic Adenocarcinoma of the Lung

Thoracic Oncology Research Laboratory, University of Pennsylvania Medical School, Philadelphia, Pennsylvania

Requests for reprints: Steven Albelda, Thoracic Oncology Research Laboratory, BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160. Phone: 215-573-9969; Fax: 215-573-4469; E-mail: Albelda{at}mail.med.upenn.edu.

Given previous work showing that an adenoviral vector expressing IFN-ß (Ad.IFNß) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 10⁹ plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNß intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNß were long-term survivors (>120 days; P < 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNß induced direct tumor cell killing and that depleting natural killer or CD8⁺ T cells, but not CD4⁺ T cells, with antibodies attenuated the effect of Ad.IFNß. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNß to treat human non–small cell lung cancer.

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